NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors.

ABSTRACT: Tyrosine kinase domains dynamically fluctuate between two main structural forms that are referred to as type I (DFG-in) or type II (DFG-out) conformations. Comprehensive data comparing type I and type II inhibitors are currently lacking for NTRK fusion-driven cancers. Here we used a type II NTRK inhibitor, altiratinib, as a model compound to investigate its inhibitory potential for larotrectinib (type I inhibitor)-resistant mutations in NTRK. Our study shows that a subset of larotrectinib-resistant NTRK1 mutations (V573M, F589L and G667C) retains sensitivity to altiratinib, while the NTRK1^V573M and xDFG motif NTRK1^G667C mutations are highly sensitive to type II inhibitors, including altiratinib, cabozantinib and foretinib. Moreover, molecular modeling suggests that th

SUBMITTER: Somwar R 

PROVIDER: S-EPMC7745027 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature